Role of Toll Like Receptor 4 in Alzheimer’s Disease
Long-term evidence has confirmed the involvement of an inflammatory component in neurodegenerative disorders including Alzheimer’s disease (AD). This view is supported, in part, by data suggesting that selected non-steroidal anti-inflammatory drugs (NSAIDs) provide protection. Additionally, molecula...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01588/full |
| _version_ | 1818299250711199744 |
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| author | Maria Calvo-Rodriguez Carmen García-Rodríguez Carlos Villalobos Lucía Núñez Lucía Núñez |
| author_facet | Maria Calvo-Rodriguez Carmen García-Rodríguez Carlos Villalobos Lucía Núñez Lucía Núñez |
| author_sort | Maria Calvo-Rodriguez |
| collection | DOAJ |
| description | Long-term evidence has confirmed the involvement of an inflammatory component in neurodegenerative disorders including Alzheimer’s disease (AD). This view is supported, in part, by data suggesting that selected non-steroidal anti-inflammatory drugs (NSAIDs) provide protection. Additionally, molecular players of the innate immune system have recently been proposed to contribute to these diseases. Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system that recognize different pathogen-derived and tissue damage-related ligands. TLR4 mediated signaling has been reported to contribute to the pathogenesis of age-related neurodegenerative diseases, including AD. Although the pathophysiology of AD is not clear, soluble aggregates (oligomers) of the amyloid β peptide (Aβo) have been proven to be key players in the pathology of AD. Among others, Aβo promote Ca2+ entry and mitochondrial Ca2+ overload leading to cell death in neurons. TLR4 has recently been found to be involved in AD but the mechanisms are unclear. Our group recently reported that lipopolysaccharide (LPS), a TLR4 receptor agonist, increases cytosolic Ca2+ concentration leading to apoptosis. Strikingly, this effect was only observed in long-term cultured primary neurons considered a model of aging neurons, but not in short-term cultured neurons resembling young neurons. These effects were significantly prevented by pharmacological blockade of TLR4 receptor signaling. Moreover, TLR4 expression in rat hippocampal neurons increased significantly in aged neurons in vitro. Therefore, molecular patterns associated with infection and/or brain cell damage may activate TLR4 and Ca2+ signaling, an effect exacerbated during neuronal aging. Here, we briefly review the data regarding the involvement of TLR4 in AD. |
| first_indexed | 2024-12-13T04:48:14Z |
| format | Article |
| id | doaj.art-69d47dccbde24783a5c23387ef7bc4a3 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T04:48:14Z |
| publishDate | 2020-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-69d47dccbde24783a5c23387ef7bc4a32022-12-21T23:59:05ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-08-011110.3389/fimmu.2020.01588552710Role of Toll Like Receptor 4 in Alzheimer’s DiseaseMaria Calvo-Rodriguez0Carmen García-Rodríguez1Carlos Villalobos2Lucía Núñez3Lucía Núñez4Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United StatesInstituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid and Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, SpainInstituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid and Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, SpainInstituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid and Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, SpainDepartamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, Valladolid, SpainLong-term evidence has confirmed the involvement of an inflammatory component in neurodegenerative disorders including Alzheimer’s disease (AD). This view is supported, in part, by data suggesting that selected non-steroidal anti-inflammatory drugs (NSAIDs) provide protection. Additionally, molecular players of the innate immune system have recently been proposed to contribute to these diseases. Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system that recognize different pathogen-derived and tissue damage-related ligands. TLR4 mediated signaling has been reported to contribute to the pathogenesis of age-related neurodegenerative diseases, including AD. Although the pathophysiology of AD is not clear, soluble aggregates (oligomers) of the amyloid β peptide (Aβo) have been proven to be key players in the pathology of AD. Among others, Aβo promote Ca2+ entry and mitochondrial Ca2+ overload leading to cell death in neurons. TLR4 has recently been found to be involved in AD but the mechanisms are unclear. Our group recently reported that lipopolysaccharide (LPS), a TLR4 receptor agonist, increases cytosolic Ca2+ concentration leading to apoptosis. Strikingly, this effect was only observed in long-term cultured primary neurons considered a model of aging neurons, but not in short-term cultured neurons resembling young neurons. These effects were significantly prevented by pharmacological blockade of TLR4 receptor signaling. Moreover, TLR4 expression in rat hippocampal neurons increased significantly in aged neurons in vitro. Therefore, molecular patterns associated with infection and/or brain cell damage may activate TLR4 and Ca2+ signaling, an effect exacerbated during neuronal aging. Here, we briefly review the data regarding the involvement of TLR4 in AD.https://www.frontiersin.org/article/10.3389/fimmu.2020.01588/fullTLR4Alzheimer’s diseasecalciumamyloid beta oligomersaginghippocampal neurons |
| spellingShingle | Maria Calvo-Rodriguez Carmen García-Rodríguez Carlos Villalobos Lucía Núñez Lucía Núñez Role of Toll Like Receptor 4 in Alzheimer’s Disease Frontiers in Immunology TLR4 Alzheimer’s disease calcium amyloid beta oligomers aging hippocampal neurons |
| title | Role of Toll Like Receptor 4 in Alzheimer’s Disease |
| title_full | Role of Toll Like Receptor 4 in Alzheimer’s Disease |
| title_fullStr | Role of Toll Like Receptor 4 in Alzheimer’s Disease |
| title_full_unstemmed | Role of Toll Like Receptor 4 in Alzheimer’s Disease |
| title_short | Role of Toll Like Receptor 4 in Alzheimer’s Disease |
| title_sort | role of toll like receptor 4 in alzheimer s disease |
| topic | TLR4 Alzheimer’s disease calcium amyloid beta oligomers aging hippocampal neurons |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01588/full |
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